Aripiprazole compositions and methods for its transdermal delivery

ABSTRACT

The present invention discloses compositions of liquid and gel formulation containing aripiprazole in the form of a patch for transdermal delivery.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation in part of PCT/US2011/057080 filedOct. 20, 2011, which claims benefit of U.S. Provisional PatentApplication Ser. No. 61/407,591 filed Oct. 28, 2010.

BACKGROUND OF THE INVENTION

1. Field of Invention

The present invention relates to the field of transdermal delivery ofpharmaceutical compositions, which have an acceptable in vitroperformance and good bioavailability. In particular, the transdermalpharmaceutical compositions of the present invention include liquids orgels of aripiprazole in a patch dosage form.

2. Background of Invention

Aripiprazole (ARPZ) is the first of a new class of atypicalantipsychotics (third generation). Biochemically, ARPZ is a partialagonist of the D2 family of dopamine receptors.^(1,2) It is activeagainst positive and negative symptoms of schizophrenia.^(3,4) ARPZ is aquinolinone derivative, white crystalline powder, practically insolublein water, with a low melting point (135-140° C.), MW 448.38 g/mole andpartition coefficient of 4.54.

All references cited herein are incorporated herein by reference intheir entireties.

BRIEF SUMMARY OF THE INVENTION

The invention provides a pharmaceutical composition comprisingaripiprazole in a dosage form for transdermal delivery, wherein thearipiprazole is in gel form, comprising: aripiprazole in the amount ofabout 1 to 20% w/v; a gelling agent in the range of about 0.1% to 5%w/v; an enhancer selected from the group consisting ofdimethylacetamide, dimethylformamide, decymethylsulfoxide, terpene andterpenoids, liposomes, niosomes, transferomes, ethanosomes, urea, lauricacid, myristc acid, and combinations thereof; wherein the pH of thecomposition is maintained at approximately 6 to 7. The invention furtherprovides a composition of the invention wherein the gelling agent ispoloxamer. The invention further provides a composition of the inventionwherein the form is a patch for transdermal delivery. The inventionfurther provides a composition of the invention wherein the dosage formis an ointment, cream, emulsion, or liposome. The invention furtherprovides a composition of the invention further comprising about 40%N-methyl-2-pyrrolidone, about 40% dimethylsulfoxide, about 15% alcohol,and about 5% water. The invention further provides a composition of theinvention further comprising ingredients selected form the groupconsisting of isopropyl alcohol, isopropyl myristate, PEG, andcombinations thereof.

The invention provides a pharmaceutical composition comprisingaripiprazole in a dosage form for transdermal delivery, wherein thearipiprazole is in liquid form, comprising: aripiprazole present in theamount of 1 to 20% w/v; an agent selected from the group consisting ofan alcohol, glycol, mineral oil, vegetable oil, and combinationsthereof, an enhancer selected from the group consisting ofdimethylacetamide, dimethylformamide, decymethylsulfoxide, terpene andterpenoids, liposomes, niosomes, transferomes, ethanosomes, urea, lauricacid, myristc acid, and combinations thereof; wherein the pH of thecomposition is maintained at approximately 6 to 7. The invention furtherprovides a composition of the invention wherein the form is a patch fortransdermal delivery. The invention further provides a composition ofthe invention being in the dosage form of an ointment, cream, emulsion,or liposome. The invention further provides a composition of theinvention further comprising about 40% N-methyl-2-pyrrolidone, about 40%dimethylsulfoxide, about 15% alcohol, and about 5% water. The inventionfurther provides a composition of the invention further comprisingingredients selected form the group consisting of isopropyl alcohol,isopropyl myristate, PEG, and combinations thereof.

The invention provides a pharmaceutical composition comprisingaripiprazole in a dosage form for transdermal delivery, wherein thearipiprazole is in gel form, comprising: aripiprazole in the amount ofabout 1 to 20% w/v; a gelling agent in the range of about 0.1% to 5%w/v; an enhancer selected from the group consisting ofdimethylacetamide, dimethylformamide, decymethylsulfoxide, terpene andterpenoids, liposomes, niosomes, transferomes, ethanosomes, urea, lauricacid, myristc acid, and combinations thereof; about 40%N-methyl-2-pyrrolidone, 40% dimethylsulfoxide, 15% alcohol and 5% water;wherein the pH of the composition is maintained at approximately 6 to 7.The invention further provides a composition of the invention furthercomprising ingredients selected form the group consisting of isopropylalcohol, isopropyl myristate, PEG, and combinations thereof.

The invention provides a pharmaceutical composition comprisingaripiprazole in a dosage form for transdermal delivery, wherein thearipiprazole is in liquid form, comprising: aripiprazole present in theamount of 1 to 20% w/v; an agent selected from the group consisting ofan alcohol, glycol, mineral oil, vegetable oil, and combinationsthereof, an enhancer selected from the group consisting ofdimethylacetamide, dimethylformamide, decymethylsulfoxide, terpene andterpenoids, liposomes, niosomes, transferomes, ethanosomes, urea, lauricacid, myristc acid, and combinations thereof; about 40%N-methyl-2-pyrrolidone, about 40% dimethylsulfoxide, about 15% alcoholand about 5% water; wherein the pH of the composition is maintained atapproximately 6 to 7. The invention further provides a composition ofthe invention further comprising ingredients selected form the groupconsisting of isopropyl alcohol, isopropyl myristate, PEG, andcombinations thereof.

The invention provides a pharmaceutical composition comprisingaripiprazole in a dosage form for transdermal delivery, wherein thearipiprazole is in gel form, comprising about 2% ARPZ; about 25% DMSO;about 10% NMP; about 5% isopropyl alcohol (IPA); about 40% EthylAlcohol; about 15% PEG 400; about 0.5% carbomer; water q.s. to 100%. Theinvention further provides a composition of the invention wherein the pHof the composition is maintained at approximately 6 to 7.

The invention provides a pharmaceutical composition comprisingaripiprazole in a dosage form for transdermal delivery, wherein thearipiprazole is in liquid form, comprising about 2% ARPZ; about 25%DMSO; about 10% NMP; about 5% isopropyl alcohol (IPA); about 40% EthylAlcohol; about 15% PEG 400; about 0.5% carbomer; water q.s. to 100%. Theinvention further provides a composition of the invention wherein the pHof the composition is maintained at approximately 6 to 7. The inventionprovides that the pH of the composition is maintained at approximately 6to 7 using HC1. The invention provides that the pH of the composition ismaintained at approximately 6 to 7 using at least one buffer.

BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS

The invention will be described in conjunction with the followingwherein:

FIG. 1 is a graph showing Effect of Drug Concentration on the Flux ofARPZ through Cellulose Membrane from 0.5% CARBOPOL® 971 Gel Systems.

FIG. 2 is a graph showing Cumulative Amount of 5% ARPZ Permeated throughCadaver Skin from 0.5% CARBOPOL® Gel System

FIG. 3 is a graph showing Cumulative Amount of Drug Permeated throughHuman Cadaver Skin from 5% ARPZ in 0.5% CARBOPOL® Gel Systems withEnhancers (Fatty Acids)

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a pharmaceutical composition comprisingaripiprazole in a dosage form for transdermal delivery. The inventionprovides a pharmaceutical composition of the invention wherein thearipiprazole is in a gel or liquid form. The invention provides apharmaceutical composition of the invention wherein the aripiprazole ispresent in the amount of 1 to 20% w/v. The invention provides apharmaceutical composition of the invention wherein the aripiprazole ispresent in the amount of 1 to 20% w/v. The invention provides apharmaceutical composition of the invention wherein the gel contains agelling agent in the range of about 0.1% to 5% w/v. The inventionprovides a pharmaceutical composition of the invention furthercomprising approximately 40% N-methyl-2-pyrrolidone, 40%Dimethylsulfoxide, 15% alcohol and 5% water.

The invention provides a pharmaceutical composition for transdermaldelivery which comprises ARPZ 2%; DMSO at a concentration of about 10 to40%, and at a preferred concentration of about 25%; NMP at aconcentration of about 5 to 40%, and a preferred concentration is about10%; Isopropyl alcohol (IPA) at a concentration of about 1 to 15%, and apreferred concentration is about 5%; Ethyl Alcohol at a concentration ofabout 15 to 40%, and a preferred concentration is about 40%; PEG 400 ata concentration of about 1 to 15%, and a preferred concentration isabout 15%; CARBOPOL® 971P at a concentration of about 0.25 to 5%, and apreferred concentration is about 0.5%; and water, q.s. to 100%.

The invention provides a pharmaceutical composition of the inventionbeing in the form of a liquid and comprising an alcohol, glycol, mineraloil, and/or vegetable oil. The invention provides a pharmaceuticalcomposition of the invention wherein the composition is in a gel formand further comprises a gelling agent selected from the group consistingof natural polymers, semisynthetic polymers, synthetic polymers,carboxyvinyl polymers or carbomers, CARBOPOL® 940, CARBOPOL® 934,CARBOPOL® 971, poloxamer, polyacrylamide, polyvinyl alcohol,polyethylene and co-polymers thereof. The invention provides apharmaceutical composition of the invention wherein the form is a patchfor transdermal delivery. The invention provides a pharmaceuticalcomposition of the invention being in the dosage form of an ointment,cream, emulsion, or liposome. The invention provides a pharmaceuticalcomposition of the invention wherein the aripiprazole is present in theamount of 1 to 20% w/v.

The invention provides a pharmaceutical composition of the inventionfurther comprising an enhancer. The invention provides a pharmaceuticalcomposition of the invention wherein the enhancer is selected from thegroup consisting of lauric acid, myristc acid, water, sulfoxides,dimethylsulfoxide, dimethylacetamide, dimethylformamide,decymethylsulfoxide, pyrrolidones, fatty acid esters, fatty acids,alcohols, fatty alcohols and glycols, urea, essential oils, terpene andterpenoids, liposomes, niosomes, transferomes and ethanosomes.

The invention provides a pharmaceutical composition of the inventionwherein the pH of the composition is maintained at approximately 6 to 7.The invention provides a pharmaceutical composition of the inventionwherein the pH of the composition is maintained at approximately 6 to 7.

The invention will be illustrated in more detail with reference to thefollowing Examples, but it should be understood that the presentinvention is not deemed to be limited thereto.

EXAMPLES Example 1

ARPZ is practically insoluble in water and has been formulated as aliquid and gel dosage form (Table 1). All reported values are inweight/volume percentage (W/V)

TABLE 1 Composition of liquid and gel formulation of Aripiprazole (5%W/V) W/V W/V N-methyl-2-pyrolidone (NMP) 40% 40% Dimethyl Sulfoxide(DMSO) 40% 40% Ethyl Alcohol 15% 15% Carbopol 971P — 0.5%  Water  5%4.5%  Total 100.00%    100.00%   

An optimal mixture design of experiments was used to select the levelsof the formulation variables. The optimum composition of a 1% W/V to 20%W/V ARPZ liquid formulation was predicted to have NMP 40%, DMSO 40%,Alcohol 15% and water 5% (Table 1). The gel formulation should contain agelling agent in the range of about 0.1% to 5% W/V and the optimum APRZcomposition should range from about 1% W/V to 20% W/V with about 0.5%W/V of the gelling agent. Therefore, the gel formulation was predictedto have a NMP of 40%, DMSO 40%, Alcohol 15%, CARBOPOL® 971 0.5%, andWater 4.5% (Table 1). However, Table 2 lists other combinations thatalso could produce successful liquid and gel ARPZ formulations inaccordance with the present invention.

TABLE 2 Concentration Ranges of N-Methyl-2-Pyrolidone (NMP), DimethlSulfoxide (DMSO), Ethyl Alcohol, and Water in Liquid AripiprazoleFormulation Formulation NMP DMSO Alcohol Water 1. 50 50 — — 2. 40 40 20— 3. 40 40 — 20 4. 40 40 15 5 5. 40 40 10 10 6. 40 40 5 15 7. 30 30 2020 8. 30 30 30 10 9. 30 40 25 5 10. 40 30 25 5 11. 45 45 10 0 12. 45 4010 5

Other than these components, other solvents known to those skilled inthe art suitable for use in the present invention can be used to preparethe liquid formulation, and combinations thereof, including but notlimited to alcohols such as but not limited to (methyl, ethyl, butyl,propyl, isopropyl, isopropyl myristate, etc.), glycols such as, but notlimited to (propylene, polyethylene, glycerin, etc.) mineral oils,vegetable oils, and others.

Example 2

The effect of gelling agents and their concentration on the permeationof ARPZ through artificial membranes and human cadaver skin wasevaluated and two characteristic graphs are shown in FIGS. 1 & 2. Theoptimal desired composition of ARPZ gel formulation contains 0.5% W/VCARBOPOL® 971. ARPZ can be gelled by gelling agents, including but notlimited to, natural polymers (such as agar, alginic acid andderivatives, cassia tora, collagen, gelatin, gellum gum, guar gum,pectin, potassium, or sodium carageenan, tragacanth, xanthan, etc.),semisynthetic polymers (such as methylcellulose, carboxymethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, etc.) syntheticpolymers (such as carboxyvinyl polymers or carbomers: CARBOPOL® 940,CARBOPOL® 934, CARBOPOL® 971, poloxamer, polyacrylamide, polyvinylalcohol, polyethylene, and its co-polymers etc), and clays (such assilicates, etc). In addition, other than cellulose membranes, ARPZ canbe evaluated with other artificial membranes including but not limitedto silicone membranes (polydimethylsiloxane), liposome-coated membranes,solid-supported liquid membranes, lecithin organogel membranes andother. Besides the gel formulations of ARPZ, other dosage formsincluding, but not limited to, ointments, creams, emulsions, liposomes,etc. may be used.

Example 3

The effect of enhancers on the flux of ARPZ through human cadaver skinwas evaluated and is shown in FIG. 3. The desired optimum composition ofARPZ gel formulation contained Lauric and Myristc acid. Apart fromLauric and Myristc acid enhancer, the ARPZ transdermal delivery can beinfluenced by enhancers including but not limited to water, sulfoxides,and similar chemicals, dimethylsulfoxide (DMSO), dimethylacetamide(DMAC), dimethylformamide (DMF), decymethylsulfoxide (DCMS) etc,pyrrolidones N-methyl-2-pyrrolidone (NMP), 2-pyrrolidon (2p), etc.,fatty acids esters (butyl ethanoate, ethyl ethanoate, ethyl oleate,isopropyl myristate, isopropyl palmiate, methyl ethanoate etc), fattyacids (capric, caprylic, lauric, oleic, myristic, linoleic, stearic,palmitic etc), alcohols, fatty alcohols and glycols (nathanol,dodecanol, propylene glycols, glycerol etc), urea, essential oils,terpene and terpenoids (limonene, thymol, cineole etc), liposomes,niosomes, transferomes, ethanosomes etc.

Example 4

The effects of pH on the permeation of ARPZ through human cadaver skinwere evaluated and a characteristic graph is shown in FIG. 2. Thepreferred optimum composition of ARPZ gel transdermal formulation had apH in the range of approximately 6 to 7. Other than these optimal pHvalues, the ARPZ transdermal delivery may be influenced by pH valuesoutside of the preferred range, but to a lesser extent. Thus, thepresent invention may still be achieved outside of the preferred pHrange of approximately 6 to 7, depending upon the circumstances of use.

The systems of this discovery can deliver ARPZ at a flux between 50mcg/ch-2. h and 800 mcg/ch-2.h, which can produce the requiredtherapeutic ARPZ blood levels. Flux rate can be changed by modifyingsuch parameters as ARPZ initial concentration, surface area of thepatch, pH of the formulation, vehicle composition, enhancer type andcomposition, etc., in accordance with the teachings of the presentinvention.

Optimum therapeutic outcome requires not only a proper drug selectionbut also an effective drug delivery. Psychotropic drug compliance ofrigorous regular medication schedules is of great importance. In manyinstances, oral administration of psychotropic agents is considered aless than optimal delivery system due to patient non-compliance⁵.Transdermal delivery of psychotropic drugs, especially with prolongedduration of action, would be valuable in increasing medicationcompliance, especially in the geriatric population. Further, potentialadvantages of ARPZ transdermal delivery are as follows: lack of hepaticfirst pass effect; eliminating the potential for over- or under-dosing;allowing the flexibility of terminating the drug administration bysimply removing the patch; providing a simplified therapeutic regimen,thereby assisting medication compliance in the geriatric population.

Example 5

A transdermal composition of Aripiprazole is shown below:

ARPZ  2% DMSO 25% NMP 10% Isopropylalcohol (IPA)  5% Ethyl Alcohol 40%PEG 400 15% Carbopol 971P 0.5%  HCl q.s. to pH 6-7 WATER q.s. to 100%

While the invention has been described in detail and with reference tospecific examples thereof, it will be apparent to one skilled in the artthat various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof.

REFERENCES

-   1. Inoue, T., Domae, M., Yamada, K., and Furukawa, T. Effects of the    novel antipsychotic agent 7-([4-2,3-dichlorophenylo-1-piperazinyl]b    Neuroutyloxyo-3,4-dihydro2 (1H)-quinolinone (OPC-14597) on prolactin    release from the rat anterior pituitary. J. Pharmacol. Exp. Ther.    1996; 277(1):137-143.-   2. Burris, K. D., Moiski, T. F., Ryan, E., Xu, C., Tottori, K.,    Kikuchi, T., Yocca, F. D, and Molinoff, P. B. Aripiprazole is a high    affinity partial agonist at human D2 dopamine receptors. Int. J.    Neuropsychopharmacol. 2000; 3(Suppl. 1), S129.-   3. Petrie, J. L., Saha, A. R., and McEvoy, J. P. Aripiprazole, a new    atypical antipsychotic: Phase II clinical trial results. Eur.    Neuropsychopharm 1997; 7 (Suppl 2): 5227.-   4. Saha, A. R., McQuade, R., Carson, W. H., Ali, M., W., Durbar, G.    C., and Ingenito, G. Efficacy and safety of Aripiprazole and    Risperidone vs. Placebo in patients with schizophrenia and    schizoaffective disorder. World J. Biol Psych 2001; 2 (Suppl 1):    305S.-   5. Geeta, A., Sanju, D., Psychotropic Drugs and Transdermal    Delivery. An Overview. Int. J. of Pharma and Bio Science, 2001; V    1(2).

What is claimed is:
 1. A pharmaceutical composition comprisingaripiprazole in a dosage form for transdermal delivery, wherein thearipiprazole is in gel form, comprising: aripiprazole in the amount ofabout 1 to 20% w/v; a gelling agent in the range of about 0.1% to 5%w/v; an enhancer selected from the group consisting ofdimethylacetamide, dimethylformamide, decymethylsulfoxide, terpene andterpenoids, liposomes, niosomes, transferomes, ethanosomes, urea, lauricacid, myristc acid, and combinations thereof; wherein the pH of thecomposition is maintained at approximately 6 to
 7. 2. The pharmaceuticalcomposition of claim 1 wherein the gelling agent is poloxamer.
 3. Thepharmaceutical composition of claim 1 wherein the form is a patch fortransdermal delivery.
 4. The pharmaceutical composition of claim 1wherein the dosage form is an ointment, cream, emulsion, or liposome. 5.The pharmaceutical composition of claim 1 further comprising about 40%N-methyl-2-pyrrolidone, about 40% dimethylsulfoxide, about 15% alcohol,and about 5% water.
 6. The pharmaceutical composition of claim 5,further comprising ingredients selected form the group consisting ofisopropyl alcohol, isopropyl myristate, PEG, and combinations thereof.7. A pharmaceutical composition comprising aripiprazole in a dosage formfor transdermal delivery, wherein the aripiprazole is in liquid form,comprising: aripiprazole present in the amount of 1 to 20% w/v; an agentselected from the group consisting of an alcohol, glycol, mineral oil,vegetable oil, and combinations thereof, an enhancer selected from thegroup consisting of dimethylacetamide, dimethylformamide,decymethylsulfoxide, terpene and terpenoids, liposomes, niosomes,transferomes, ethanosomes, urea, lauric acid, myristc acid, andcombinations thereof; wherein the pH of the composition is maintained atapproximately 6 to
 7. 8. The pharmaceutical composition of claim 7wherein the form is a patch for transdermal delivery.
 9. Thepharmaceutical composition of claim 7 being in the dosage form of anointment, cream, emulsion, or liposome.
 10. The pharmaceuticalcomposition of claim 7 further comprising about 40%N-methyl-2-pyrrolidone, about 40% dimethylsulfoxide, about 15% alcohol,and about 5% water.
 11. The pharmaceutical composition of claim 10,further comprising ingredients selected form the group consisting ofisopropyl alcohol, isopropyl myristate, PEG, and combinations thereof.12. A pharmaceutical composition comprising aripiprazole in a dosageform for transdermal delivery, wherein the aripiprazole is in gel form,comprising: aripiprazole in the amount of about 1 to 20% w/v; a gellingagent in the range of about 0.1% to 5% w/v; an enhancer selected fromthe group consisting of dimethylacetamide, dimethylformamide,decymethylsulfoxide, terpene and terpenoids, liposomes, niosomes,transferomes, ethanosomes, urea, lauric acid, myristc acid, andcombinations thereof; about 40% N-methyl-2-pyrrolidone, 40%dimethylsulfoxide, 15% alcohol and 5% water; wherein the pH of thecomposition is maintained at approximately 6 to
 7. 13. Thepharmaceutical composition of claim 12, further comprising ingredientsselected form the group consisting of isopropyl alcohol, isopropylmyristate, PEG, and combinations thereof.
 14. A pharmaceuticalcomposition comprising aripiprazole in a dosage form for transdermaldelivery, wherein the aripiprazole is in liquid form, comprising:aripiprazole present in the amount of 1 to 20% w/v; an agent selectedfrom the group consisting of an alcohol, glycol, mineral oil, vegetableoil, and combinations thereof, an enhancer selected from the groupconsisting of dimethylacetamide, dimethylformamide, decymethylsulfoxide,terpene and terpenoids, liposomes, niosomes, transferomes, ethanosomes,urea, lauric acid, myristc acid, and combinations thereof; about 40%N-methyl-2-pyrrolidone, about 40% dimethylsulfoxide, about 15% alcoholand about 5% water; wherein the pH of the composition is maintained atapproximately 6 to
 7. 15. The pharmaceutical composition of claim 14,further comprising ingredients selected form the group consisting ofisopropyl alcohol, isopropyl myristate, PEG, and combinations thereof.16. A pharmaceutical composition comprising aripiprazole in a dosageform for transdermal delivery, wherein the aripiprazole is in gel form,comprising about 2% ARPZ; about 25% DMSO; about 10% NMP; about 5%isopropyl alcohol (IPA); about 40% Ethyl Alcohol; about 15% PEG 400;about 0.5% carbomer; water q.s. to 100%.
 17. The pharmaceuticalcomposition of claim 16, wherein the pH of the composition is maintainedat approximately 6 to
 7. 18. A pharmaceutical composition comprisingaripiprazole in a dosage form for transdermal delivery, wherein thearipiprazole is in liquid form, comprising about 2% ARPZ; about 25%DMSO; about 10% NMP; about 5% isopropyl alcohol (IPA); about 40% EthylAlcohol; about 15% PEG 400; about 0.5% carbomer; water q.s. to 100%. 19.The pharmaceutical composition of claim 18, wherein the pH of thecomposition is maintained at approximately 6 to 7.